New funding puts Viral Vector Manufacturing Facility in winning position

Children’s Medical Research Institute warmly welcomes the NSW Government’s announcement of its allocation in the 2022/23 Budget of $101.4m toward a commercial-scale Viral Vector Manufacturing Facility. This significant investment will greatly advance the ability to treat children with serious genetic diseases.

In addition to funds to build the manufacturing facility, the $101.4 million commitment includes operational funding to accelerate NSW’s commercial-scale viral vector production.

NSW Premier, The Hon Dominic Perrottet announced the Viral Vector Manufacturing Facility funding as part of a total $270m investment toward boosting biomedical research and Med Tech innovation.

CMRI’s Head of Gene Therapy, Professor Ian Alexander, who is involved in the Viral Vector program, said, “This funding is very timely given the explosion of therapeutic possibilities emerging from the gene therapy field. Close to 90% of these therapies require viral vector manufacture to reach human clinical trials and beyond.”

Head of CMRI’s Translational Vectorology Unit, Associate Professor Leszek Lisowski, said, “The real work starts now, and this funding from the NSW Government puts us in a winning position.’’

A vector is a microscopic tool used to deliver healthy copies of genes to patients’ tissues and organs, or to deliver the ability to correct the genetic error at its source. While the technology is developing rapidly, the ability to produce high-quality (clinical grade) vectors has been a roadblock until now.

NSW is at the forefront of international gene therapy research through the pioneering work of researchers at CMRI and their colleagues in the Luminesce Alliance of paediatric research organisations. The availability of clinical-grade viral vector production capability in Australia, located next door to CMRI, will accelerate the ability to translate CMRI’s research into the clinic – as potential cures for serious genetic diseases affecting children.

This Viral Vector Manufacturing Facility located in the Westmead Health and Innovation Precinct is a collaboration between NSW Treasury, Investment NSW, and various NSW Health entities, including Health Infrastructure, Office of Health and Medical Research, Sydney Children’s Hospitals Network and with support from Children’s Medical Research Institute and Western Sydney Local Health District.

The NSW Government’s $270m funding package also includes $143.3 m for the Sydney Biomedical Accelerator at Camperdown and $25.6 m for advanced therapies such as CAR T-cell therapies for cancer.

CMRI’s Director, Professor Roger Reddel, welcomed all of this news and thanked the NSW Government and the Ministry of Health for its commitment to making lifesaving treatments available to the people of this State as early as possible.

“We are in the early phases of a revolution in medical technology that will make it possible to treat and even cure serious diseases, especially of children, that currently have no or very limited treatment options. This is already happening for a small number of inherited diseases, and there is enormous potential to extend this technology further to benefit children and adults with many more inherited diseases and other diseases such as cancer. The major investment announced by the NSW Government is a critically important step towards making this a reality,” Prof Reddel said.

Gene Therapy Improvement Has Massive Potential

A team of scientists from Children’s Medical Research Institute (CMRI) in Sydney have developed a new way to improve targeting of specific organs and tissue types in gene therapy – making this innovative gene delivery technology more efficient and described as having “massive potential’’ for the field.

The work is featured as the cover story in the scientific journal, Human Gene Therapy published this week.

Tools based on adeno-associated virus (AAV), a non-pathogenic virus, are used as a delivery system for gene therapeutics. To convert the virus into a delivery tool, the researchers have removed all viral genes, which turns the virus into a very efficient gene delivery vehicle, called a vector. The vector can then be used to deliver a working copy of a gene to specific cells in the patient to correct a disease caused by a faulty gene. With one injection, patients could potentially be cured of their disease.

However, this system is still in the early stages of development for many conditions. One of the major limitations is the ability to safely and effectively deliver the therapeutic gene to the specific (diseased) cells inside the patient’s body; something the current generation of viral vectors are not able to achieve. Novel bioengineered AAV vectors developed with the clinical application in mind, offer a promising alternative. The CMRI team specialises in the development of novel AAV vectors. The first bioengineered AAV vector to enter clinical development (currently in number of a commercial and academic trials, including Phase III for a genetic liver condition) was developed by the CMRI team in collaboration with Stanford University.

In this publication, the CMRI team reports a new method that enables the development of more functional and improved AAV vectors. In contrast to other commonly used vector bioengineering methods, the technology developed by the CMRI team allows the researchers to select the best novel vector, based on how well it is likely to restore gene function in a therapeutic application.

“We successfully optimised an existing technology to generate new AAV capsids to be able to target new organs, or target organs that are already accessible to gene therapy, more efficiently,’’ says the lead author Adrian Westhaus who is part of CMRI’s Translational Vectorology Research Unit.

“The optimisation was achieved by understanding an existing promoter element in the AAV genome and repurposing it for viral capsid engineering.’’ A promoter is “an engine” that drives expression of genes.

Head of the Translational Vectorology Research Unit, Associate Professor Leszek Lisowski, said it was an exciting new platform technology.

“This will allow us to develop, right here in Australia, even better novel AAVs that will enter translational development pathways, with the promise of being better carriers of gene therapeutics.”

“It will bring hope of effective treatment to millions of kids affected by genetic disorders. The technology has enormous potential, and while its full impact is difficult to predict, it could form the foundation of a revolution in biomedical and translational research.”

“This innovative approach, referred to as the functional transduction (FT)-based method for rapid identification of novel AAV variants, has the potential to improve the development of treatments for all conditions that could benefit from AAV-mediated gene therapy.” Says Dr Marti Cabanes-Creus, the inventor of the technology.

The teams involved were CMRI’s Translational Vectorology Unit, the Gene Therapy Research Unit, along with the Stem Cell Medicine Group which produced an image selected for the cover of Human Gene Therapy. Authors were Adrian Westhaus, Dr Marti Cabanes-Creus, Timo Jonker, Erwan Sallard, Renina Gale Navarro, Erhua Zhu, Grober Baltazar Torres, Scott Lee, Patrick Wilmott, Dr Anai Gonzalez-Cordero, Professor Ian Alexander, and Associate Professor Leszek Lisowski.

The work was funded by Australian National Health and Medical Research Council, the Paediatric Precision Medicine Program, Luminesce Alliance and LogicBio Therapeutics.

The publication is available online here: https://www.liebertpub.com/doi/full/10.1089/hum.2021.278

Partnership for RNA Project

Scientists from Children’s Medical Research Institute (CMRI) have partnered with RNA researchers from the Monash Institute of Pharmaceutical Sciences (MIPS) to combine mRNA delivery with viral gene delivery to treat metabolic liver disease in infants and children.

The partnership will be funded by a $99k grant from the mRNA Victoria Research Acceleration Fund along with grants from Monash University and CMRI, and will be led by Professor Colin Pouton from MIPS alongside Dr Samantha Ginn and Professor Ian Alexander from CMRI’s Gene Therapy Research Unit.

The MIPS team is also made up of mRNA researchers, Dr Harry Al-Wassiti, Dr Joan Ho and Dr Stewart Fabb.

For several years, CMRI’s Dr Ginn and Professor Alexander (also of Sydney Children’s Hospital Network) have been working on gene editing using CRISPR-Cas9 (a family of DNA sequences) with the aim to directly repair defective genes in infants and children with ornithine transcarbamylase (OTC) deficiency, a genetic disorder that can lead to progressive liver damage.

“We are thrilled to be working with Professor Colin Pouton, Dr Harry Al-Wassiti and the team from Monash to develop gene therapy treatments for children with genetic liver disease,’’ Dr Ginn said. This is made possible by our combined expertise in gene delivery and genome editing technology and this grant will enable us to continue our efforts in this space.”

Professor Pouton’s team at MIPS has partnered with the CMRI team to make CRISPR-Cas9 gene correction safer by using mRNA technology, with preliminary experiments producing some very exciting data.

Professor Pouton, who is also leading the development of Australia’s first mRNA COVID-19 vaccine, said it’s an exciting time for mRNA technology and its potential to transcend a broad range of medical applications.

“It’s very encouraging to see Australia continue to build its capabilities in mRNA research, development and manufacturing, which all contribute towards building a sustainable end-to-end ecosystem for producing world-leading RNA-based medical products,” Professor Pouton said.

“This grant will enable the two groups to combine expertise in mRNA and gene editing to develop a technological platform for gene correction with broad therapeutic applicability and a universal therapeutic approach to the treatment of infants and children with OTC deficiency.”

New research facility to deliver life-saving medical technology in Western Sydney

CMRI is delighted by the NSW Government’s announcement about the establishment of Australia’s ​first commercial-scale viral vector manufacturing facility in the Westmead Health and Innovation District.

The ability to manufacture high-quality (clinical grade) viral vectors in Australia is critically important for our gene therapy programs. It will accelerate the delivery of, and access to, life-saving new gene therapies developed in the CMRI labs led by Professor Ian Alexander, Associate Professor Leszek Lisowski, Dr Anai Gonzalez-Cordero and Professor Robyn Jamieson, with our partner organisation, SCHN, to Australian patients, and transform the lives of many Australian families.  

Research Collaboration Announced Between CMRI and DiNAQOR to Develop Novel, Cardiac Specific Capsids

ZURICH-SCHLIEREN, Switzerland and WESTMEAD, NSW, Australia, Jan. 10, 2022 /PRNewswire/ — DiNAQOR, a genetic medicine platform company focused on addressing severe inherited cardiac diseases, today announced it has entered into a research collaboration with Children’s Medical Research Institute (CMRI) in Australia to develop novel bioengineered adeno-associated virus (AAV) capsids to route gene therapy directly to human cardiac muscle.

Under the terms of the agreement, DiNAQOR has the option to obtain an exclusive license for capsids co-developed with CMRI for both cardiovascular and kidney diseases. As part of the collaboration, CMRI will make available its extensive library of AAV capsids, which are the protein shells surrounding viruses that act as a delivery mechanism for gene therapies. DiNAQOR will provide access to its proprietary engineered heart tissue (EHT) technology and animal tissue to enable the most effective and clinically-impactful screen of the CMRI capsids to identify novel cardiac-specific capsid variants.

“We are honored to be working closely with CMRI, a pioneer in the field of gene therapy and a world leader in the design of capsids to deliver these medicines,” said Eduard Ayuso, D.V.M., Ph.D., Chief Technology Officer at DiNAQOR. “Our aim is to develop new capsids that can target the heart more efficiently at lower doses.”

DiNAQOR will screen capsids for transduction systemically and tailor AAV capsids for loco-regional perfusion (LRP) administration. DiNAQOR’s LRP system enables gene therapies to be routed directly to the cardiac muscle, maximizing biodistribution and transduction of the cardiac cells. This new approach, which is actively being used in several pre-clinical studies, may minimize potential adverse effects of systemic gene therapy delivery while lowering the cost.

“This will be an exciting collaboration, and it is consistent with our strategy to align with world leading academic institutions to expand our R&D efforts, platform capabilities and our pipeline,” said Johannes Holzmeister, M.D., Chairman and CEO of DiNAQOR. “CMRI has a stellar team, and we look forward to working closely with them to make a real difference in the lives of patients.”

The CMRI team is led by Associate Professor Leszek Lisowski, Ph.D., MBA, an expert in viral vector-based gene therapies, vectorology and genotoxicity.

“We look forward to working with the team at DiNAQOR to identify novel capsids that may improve the standard of care for patients with heart disease,” commented Associate Professor Lisowski. “We are optimistic that novel capsids, administered with DiNAQOR’s LRP system, will form a foundation of novel advanced therapies to benefit millions of affected patients world-wide.”

About Children’s Medical Research Institute
Children’s Medical Research Institute (CMRI) is an award-winning state-of-the-art medical research facility, dedicated to researching the genes and proteins important for health and human development. CMRI is supported in part by its key fundraiser Jeans for Genes®. CMRI is located at Westmead, the largest health and medical research precinct in NSW, Australia, and is affiliated with the University of Sydney.

About DiNAQOR
DiNAQOR is a genetic medicine platform company focused on advancing novel solutions for patients suffering from severe, inherited forms of heart disease. The company is headquartered in Zurich-Schlieren, Switzerland, with additional presence in London, England; Hamburg, Germany; and Laguna Hills, California. For more information visit www.dinaqor.com.

Australian first gene therapy for childhood blindness

Two Sydney siblings have become the first patients in the country to receive a novel gene therapy that has rescued their vision and holds hope for preventing them from going blind.

The ocular gene therapy, LUXTURNA, is the world’s first approved gene replacement therapy for an inherited blinding eye condition and one of the first gene replacements for any human disease. Approved by the Therapeutic Goods Administration, LUXTURNA is used to treat children and adults with biallelic pathological mutations in RPE65, a rare mutation that leads to vision loss and blindness. It is being distributed in Australia by Novartis.

Seventeen-year-old Rylee and 15-year-old Saman were both diagnosed with Leber congenital amaurosis, a severe form of retinal dystrophy, in their first year of life. They received the life-changing therapy at The Children’s Hospital at Westmead in late 2020 and early 2021. The therapy has stopped their progressive vision loss and led to some improvements in their vision.

The therapy was delivered as part of Ocular Gene and Cell Therapies Australia (OGCTA), a new collaboration involving the Genetic Eye Clinic at Sydney Children’s Hospitals Network (SCHN), the Eye Genetics Research Unit and Stem Cell Medicine Group at the Children’s Medical Research Institute (CMRI), and the Save Sight Institute at Sydney Eye Hospital and University of Sydney.

CMRI was represented on this project by Professor Frank Martin who is CMRI’s Board President, Professor Robyn Jamieson who is Head of the Eye Genetics Research Unit at CMRI and SCHN and Dr Anai Gonzalez Cordero who is Head of the Stem Cell Medicine Group.

Prof Robyn Jamieson and Dr Anai Gonzalez Cordero

Professor Jamieson is also lead of OGCTA and Head, Specialty of Genomic Medicine, University of Sydney. She said the therapy was revolutionary and would lead to transformation of care for patients with blinding eye diseases.

“Inherited retinal disease is a devastating diagnosis. Up until now, these patients suffered progressive vision loss that led to blindness and there was no therapy for them at all,” Professor Jamieson said.

“But through new genomic diagnostics and the use of ocular gene therapy, we are finding that we have the ability to not only stop this ongoing progression but also help to improve vision for people who have RPE65-related retinal vision loss.”

Children and adults born with a mutation in both copies of the RPE65 gene can suffer from a range of symptoms, including night blindness (nyctalopia), loss of light sensitivity, loss of peripheral vision, loss of sharpness or clarity of vision and potentially total blindness.

Ocular gene therapy works by injecting LUXTURNA under the retina and carrying a functioning RPE65 gene to replace the faulty one, thereby preventing some of these devastating symptoms.

“The real-world improvements in visual function has been quite remarkable bringing to life the rather dry clinical trials outcome measures. It is tremendously heartening to see the changes in vision capabilities for these first patients treated with LUXTURNA, Professor John Grigg, Head of Specialty of Ophthalmology, Save Sight Institute, University of Sydney and lead inherited retinal disease specialist in OGTCA said.

“As an ophthalmologist who has been caring for patients with Leber’s amaurosis for many years and unable to offer any treatment, it is incredibly rewarding to now have the opportunity to not only give families hope but also be involved in improving their child’s vision,” Frank Martin, Clinical Professor in the Specialties of Paediatrics and Child Health and Ophthalmology at the University of Sydney said. 

Frank Martin
Prof Frank Martin

Associate Professor Matthew Simunovic, Vitreoretinal Surgeon, Sydney Eye Hospital and SCHN and Associate Professor at the Save Sight Institute, University of Sydney performed the first surgery and said the benefits of treatment should extend well into the future:

“This is incredibly delicate surgery in which LUXTURNA is injected under the retina, which in some patients can be as thin as a sheet of copy paper. Riley and Saman have had profound improvements in their vision, which mirror the results seen in the pivotal clinical trials. Importantly, such benefits appear to be sustained for many years – in fact, for as long as patients have been followed up. Successfully delivering the first approved gene therapy has been a fantastic team effort, and it underscores Australia’s capability in this field” A/Prof. Simunovic said.

To date, this treatment has been used to treat four patients and while it can only be used to treat this specific form of retinal disease, it does provide significant hope that similar treatments will be able to be applied to other retinal disease genes in the future.

“This heralds a new era in transforming the lives of these people who otherwise have a life of blindness ahead of them and provides hope for more than 15,000 other affected Australians who live with some form of inherited retinal disease,” Professor Grigg said.

READ THE ABC STORY ON THIS NEWS HERE: https://www.abc.net.au/news/20…

CMRI Awarded Multiple Medical Research Future Fund Grants

Children’s Medical Research Institute (CMRI) was awarded multiple Medical Research Future Fund (MRFF) grants to help improve the lives of children living with genetic diseases. The MRFF, which is an initiative of the Australian Government, has funded research projects in cancer, gene therapy, and stem cell medicine at CMRI.

Dr Anai Gonzalez-Cordero, head of the Stem Cell and Organoid Facility and Stem Cell Medicine Group at CMRI, has been awarded the MRFF Stem Cell Therapies Grant to investigate new gene therapies for inherited eye disease.

Dr Gonzalez-Cordero and her team, in collaboration with A/Prof Leszek Lisowski and Prof Robyn Jamieson, Prof Ian Alexander, and Prof John Grigg (of SCHN and CMRI), as well as Dr Carvalho at the Lei Institute in WA, will collect induced pluripotent stem cells (iPSC) from patients’ own cells to generate mini-organs (3-dimensional organoids), specifically of the retina. Thanks to the $498,000 award from the MRFF, Dr Gonzalez-Cordero will be able to test new gene therapies on these retinal organoids and try to reverse the blinding effects of inherited eye disease.

A key tool in gene therapies is the use of adeno-associated virus (AAV) vectors. Where Dr Gonzalez-Cordero will use an AAV vector to treat blindness, Associate Professor Leszek Lisowski, head of the Vector and Genome Engineering Facility and Translational Vectorology Unit at CMRI, will attempt to treat Friedreich’s Ataxia, a genetic disease that causes progressive nervous system damage and movement problems.

A problem with the AAV vector is its difficulty in targeting neuronal and cardiac cells, making them ineffective in the treatment of neurological diseases like Friedreich’s Ataxia. A/Prof Lisowski, in collaboration with Associate Professor Mirella Dottori from the University of Wollongong, was awarded $983,000 to address this major roadblock and develop superior AAV vectors (called ‘SMART AAVs’) that specifically target human cardiac cells, sensory neurons and cerebellar neurons.

Professor Hilda Pickett and her team have long investigated telomeres, the short DNA stretches located at the ends of chromosomes that are important to cancer and aging. Unlike normal cells, where telomeres shorten every time a cell divides, the telomeres in cancer cells maintain their lengths, enabling them to keep growing. There are two methods cancer cells use to achieve this: telomerase and the Alternative Lengthening of Telomeres (ALT) mechanism.

Osteosarcoma is the most common type of primary bone malignancy, with the highest incidence in adolescence. The ALT mechanism is used by nearly 60% of osteosarcomas, yet no ALT-specific treatment strategies currently exist. Courtesy of a $1.48 million grant, Prof Pickett and her collaborators on this project (Prof Roger Reddel and A/Prof Tony Cesare of CMRI) can exploit a newly found Achilles’ heel of ALT cells to create chemical inhibitors toxic to ALT cells, improving treatments for adolescent osteosarcomas.

The Australian Government has contributed $2,961,000 in total to research at CMRI through these MRFF grants, and their support is a huge step towards beating children’s genetic diseases.

Learn more about the MRFF at http://www.health.gov.au/mrff

Dr Anai Gonzalez-Cordero, A/Prof Leszek Lisowski, Prof Hilda Pickett, Prof Robyn Jamieson, Prof Ian Alexander, Prof Roger Reddel, A/Prof Tony Cesare

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Gene therapy trial success: game changer for children with SMA

New research has shown that gene therapy may provide an effective treatment for Spinal Muscular Atrophy (SMA), a devastating and fatal genetic condition. The first part of the results from the SPR1NT trial were presented at the European Academy of Neurology (EAN) Conference recently. 

What is SMA?

SMA affects the motor nerve cells in the spinal cord, causing progressive muscle weakness and preventing babies from being able to roll, sit up, crawl, walk and eventually breathe. Until recently, it was the leading genetic cause of infant death in Australia, occurring in 1 in every 10,000 births.

Global recruitment site for trial

Sydney Children’s Hospitals Network (SCHN) was the only Australian site selected to participate in the trial and was one of the largest global recruitment sites, with four patients enrolled from SCHN. The trial investigated the use of Zolgensma, a novel viral vector-based gene replacement therapy. Fourteen infants, under six weeks of age and at risk of developing the most common and severe form of SMA, were treated before their symptoms started. 

Successful results

The study, which followed each participant until aged 18 months, found that all children achieved the ability to sit independently (with 78 per cent achieving this milestone within the normal developmental window), all were alive and free of permanent ventilation and all had normal swallow function and were fed exclusively by mouth by 18 months of age. The trial also showed that following treatment nine children were able to walk independently and all showed fine motor performance similar to babies without SMA by the completion of the study. 

Site-based lead for the study and Paediatric Neurologist at Sydney Children’s Hospital, Randwick, A/Prof Michelle Farrar said the results of the trial was a potential game-changer for both clinicians and families affected by SMA. “These results are extremely exciting and encouraging, not only are these children surviving but with this therapy, most are meeting the developmental milestones of any normal baby, which is unheard of.”

Zolgensma works by treating SMA at its root cause, inserting a functioning copy of the defective gene into the cells.

“By identifying these infants with SMA before the onset of symptoms, early results suggest we may have been able to take what was considered a lethal disease, and turn that around with a one-time, single dose infusion.

“It is giving life back to these babies and hope back to their families.”

Since the introduction of SMA into the newborn screening program in 2018, more than 200,000 babies have been screened, which has helped significantly with early identification of the condition.

In addition to the newborn screening program, the NSW Government has invested $25 million to boost the state’s capability to manufacture viral vectors – the key components of this type of therapy which holds great promise for novel treatments for other genetic diseases.

The second part of the SPR1NT trial, which explored the effect of Zolgensma® in babies with milder SMA, is due to be presented later this year.

Click here for the full media release.

The SPR1NT trial was also supported by Luminesce Alliance and partners including UNSW Sydney.


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Scientists from Children's Medical Research Institute (CMRI) have partnered with RNA researchers …
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CMRI is delighted by the NSW Government’s announcement about the establishment of Australia's ​first commercial-scale viral vector …

CMRI announces new collaboration with Gyroscope Therapeutics

Children’s Medical Research Institute and Gyroscope Therapeutics Holdings, a clinical-stage gene therapy company focused on treating diseases of the eye, today announced they have entered a research collaboration to develop next-generation clinical capsids, the protein shells of viral vectors used to deliver gene therapies.

A team of researchers from CMRI and Gyroscope will work together in the design and screening of capsid libraries to identify novel capsids for enhanced delivery of ocular gene therapies. Under the agreement, Gyroscope has an option to obtain an exclusive licence for ocular uses of capsids developed through the partnership. The CMRI team is led by Associate Professor Leszek Lisowski, Ph.D., MBA, a recognised expert in viral vector-based gene therapy, vectorology and genotoxicity, with more than 15 years of experience in capsid generation and discovery.

“Capsids are one of the most critical components of a gene therapy, however, there are some limitations with the capsids available today,” said Jane Hughes, Ph.D., Chief Scientific Officer, Gyroscope. “We are excited to collaborate with Associate Professor Lisowksi and the team at CMRI to engineer next- generation capsids supporting our goal of developing a pipeline of differentiated ocular gene therapies that have the potential to be administered in the convenience of a doctor’s office.”

“Gene therapies are being studied in many diseases of the eye and capsids play an important role in maximising the potential benefit of these therapies for patients,” said Associate Professor Lisowski. “We look forward to working with the team at Gyroscope to identify novel capsids that may improve upon the current standard for gene therapies for treatment of diseases of the eye.”

Associate Professor Leszek Lisowski will lead Dr Marti Cabanes Creus and Dr Carolin Von Lupin from CMRI’s Translational Vectorology Unit on this project and will also work closely with the Head of CMRI’s Stem Cell Medicine Group Leader Dr Anai Gonzalez Cordero.

Gene therapy project ranked top idea in Australia

A gene therapy project to save infants’ lives has been named the top ranked National Health and Medical Research Council (NHMRC) Ideas Grant for 2020, in what the lead researcher describes as ‘proof that we weren’t just dreamers and symbolic of the power of the genomic revolution’.

Professor Ian Alexander and his team were awarded the 2020 NHMRC Marshall and Warren Ideas Grant Award at the NHMRC Research Excellence Awards Dinner on 16 June.

Professor Alexander is Head of the Gene Therapy Research Unit, a joint initiative of Children’s Medical Research Institute (CMRI) and The Sydney Children’s Hospitals Network (SCHN), and Professor in Paediatrics and Molecular Medicine at the University of Sydney.

His team’s work, over more than 25 years, has made significant contributions to the field of gene therapy and is now leading major advances in treatments for life-threatening genetic diseases.

“The gene therapy field is coming of age and earning the scientific respect that it has increasingly deserved. I thank the NHMRC for this award, which is emblematic of the explosion of therapeutic possibilities – which are unlimited,” Professor Alexander said.

Gene therapies are ‘genetic medicines’ where healthy copies of genes are delivered into diseased cells to replace or repair faulty genes and therefore treat (or potentially cure) disease. The delivery vehicle for the healthy gene is called a vector (typically modified viruses such as adeno-associated virus (AAV)).

This three-year NHMRC-awarded project aims to exploit immunity to the AAV vector that is stimulated in infants receiving gene therapy for Spinal Muscular Atrophy (SMA), and to use this to engineer the next generation of vectors.

SMA is an inherited neuromuscular disorder, which can be fatal. Babies often die within the first 2 years of life. NSW/ACT are among a few places in the world where there is now pilot newborn screening for SMA, supported by the NSW Government.

The clinical team at SCHN (incorporating experts from The Children’s Hospital at Westmead and Sydney Children’s Hospital, Randwick) has become a leading global centre in using AAV-based viral vectors in gene therapy for infants with SMA, with unprecedented success.

“This award is linked to the fact that we are at the front end of seeing the impact of the genomic revolution,’’ Professor Alexander said.

“It heralds our ability to treat disease by gene transfer. The most stunning example being the treatment of SMA in infants.

“We are now trying to go beyond that. This takes it a step further to improve the technology available to patients – to be able to treat more children, and not just children with SMA. The success of the SMA trials is not the end, it’s just the beginning. There is so much powerful science that can be leveraged by this progress.”

The team is now looking at ways to identify what antibodies the children are producing against the SMA gene therapy vector, recover these antibodies by reverse engineering, and to use these antibodies to guide re-engineering of efficient AAV vectors that can evade immunity. This would help the proportion of children who develop natural immunity to AAV and for whom the original SMA gene therapy is therefore ineffective.

“In this way we can use a child’s immune response to both improve the technology and enhance the treatment opportunities,’’ Professor Alexander said.

“This is a very powerful approach that has many implications, for neurological conditions and beyond.’

“Success breeds success. There is a very fertile interface between clinical medicine and discovery science, and this shows that deep science can emerge from privileged access to clinical material.’’

The project’s other lead investigator is Dr Grant Logan from Children’s Medical Research Institute. Associate investigators are Associate Professor Leszek Lisowski (CMRI), Associate Professor Michelle Farrar (SCHN and the University of NSW), Professor Daniel Christ and Dr Joanne Reed (Garvan Institute for Medical Research), and Dr Denis Bauer (CSIRO).

Listen to ABC Interview

2020 NHMRC Research Excellence Award Winners

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